Process of obtaining an effective ergot preparation



Filed March 17, 1934 -June l, 1937. M s KHARAscH ET AL PROCESS OF OBTAINING AN EFFECTIVE ERGOT PREPARATION Patented June 1, 1937 PROCESS 0F OBTAINING AN EFFECTIVE ERGOT PREPARATION Morris S. Kharasch and Romeo Ralph Legault, Chicago, Ill., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana Application March 17,

4 Claims.

It is the object of our invention to obtain ergot alkaloids which are stable, which can be administered in solid form as well as in solution, and which have a physiological effect which permits their safe administration under certain conditions when it is unsafe to administer the ordinary ergot products, especially just prior to labor; Vand which can be obtained with large yields from the original ergot.

It is a further object of our invention to obtain an ergot product free from the disagreeable taste characteristic of U.'S. P. ergot; and, furthermore, an ergot extract which contains more of the active principle of ergot per unit of weight than is obtained by the ordinary U. S. P. method.

Our invention involves both a new method and a new product.

Fundamentally, our method involves an extraction of ergot, desirably although not necessarily after certain undesirable fractions thereof have been removed by other means, by substantially dry liquid sulphur dioxide, at rather low temperature. While the particular type of extraction apparatus is immaterial, we prefer one which produces a continuous and repeated percolation of liquid sulphur dioxide through the ergot; such as a modied Soxhlet apparatus, in which liquid sulphur dioxide in the Soxhlet receiver is vaporized, the vapor rises to a cooling column at which it is recondensed into liquid phase and from which the liqueed sulphur dioxide drops back through a porous container which contains the ergot being extracted and thence intothe Soxhlet receiver. 'I'he cooling column is kept sufciently cool in any convenient manner, as by being immersed in liquid ammonia.

The sulphur-dioxide extract thus obtained is rich in ergot alkaloids, which may readily be obtained in solid form by simple evaporation of the sulphur dioxide. These ergot alkaloids as thus obtained have certain advantages over previously known ergot preparations, as will appear.

The extraction of ergot by sulphur dioxide has a number of deiinite advantages, among which are:

l. 'I'he extraction is at low temperature, so that the relatively destructive effects of higher temperature extraction are avoided.

2. I'he extracting solvent is acidic in character; and this avoids diiiiculties inherent in the use of alkaline extracting solvents, and makes for stability of the product.

3. The extracting solvent tends to retard if 1934, Lserial No. 716,158

(o1. sil-z8) ergot, as against 0.7 to 0.9 milligram by earlier methods.

7. The taste of the material ir. the form of a uid extract has none of the unpleasant qualities characteristic of the U. S. P. product.

8. The sulphur dioxide extracts less of the extraneous materials present in ergot, and therefore weight for weight the solid obtained by this method is more eiective than is that obtained by evaporation of the iluid extract ofy ergot prepared according to the U. S. P. method. In fact our extract per unit of activity contains only one-fteenth'to one-twentieth of the total solids obtained by the U. S. P. method.

9. Perhaps most important of all, our experiments indicate that the ergot alkaloids obtained by sulphur-dioxide extraction, when administered by mouth either with or without an enteric coating, produce a character of uterine contraction which has certain unique properties; in that although the contractions are produced as with other ergot preparations, there is not produced the elevation of the basal line which other ergot preparations give and which make such other ergot preparations unsafe to administer at certain periods. In other words, our ergot preparation causes rhythmic contraction of the uterus, as other ergot preparations also do; but it allows complete relaxation between uterine contractions, which is not the case with previously known ergot preparations. Therefore, a material obtained by our process can be used with both safety and advantage prior to delivery; which is now considered unsafe with other ergot preparations because of the elevation produced in the basal line.

The accompanying drawing will aid in an understanding of our invention. In such drawing, Fig. 1 is a vertical central section, somewhat schematic, of a modified Soxhlet apparatus which we have found effective for carrying out our process of extraction; Fig. 2 is a kymograph chart showing the general character of uterine contractions produced by prior ergot preparations; and Fig. 3 is another kymograph chart showingthegeneralcharacterofuterinecontractions produced by our ergot preparation.

The modified Soxhlet apparatus shown in Fig. l lus three main portions-a condenser Il, an

l extractor Il,and areceiver i2.

'Die extractor II is provided with the usual Boxhlet thimble i3 of porous paper, which is filledtothedesiredlevel withthe ergot Iltobe extracted. The extractor Il is provided near the lobottom with an outlet passage II for the extract; and this outlet passage extends rst upwardtothelevelrat whichitis desiredtomaintain the liquid level I6 in the extractor li, and thence downward into and downward within the litube II bywhichthe extractor Il ismountedin themouthofthereceiver l2. Thetube llnear ihtopopens intoalateralpsage Il` whichleads totheupperpartof theextractor Il,abovethe liquidleveltherein. Thereceiverl2maybesuitahlyheatelLwhenandifdesired. asbythe heat ofanincandescent lamp I0.

Theupperendoftheextractor I Iisconnected tothelowerendof the condensertube Il, which isprwidedwithajacketforholdinganysuitaliblecoolingliquid. Whena cooling liquid is used whichhasaverylow boiling point, suchasliquid ammouia,itisdesirable thattheiacketnbca double-walled vacuum jacket, of the Dewar type, with'an open top; and it is also desirable to have Ssomehrmpsn ofsilicagel inthebottom ofthe jacket. to'prevent bumping.

The upper endof the condenser tube Il is provided with an inlet valve 22; and desirably with a lateral outlet passage 23 to avoid having a closed system. 'Iheoutletpassage 2Imayleadtoa suitable absorption system.

In carrying out our process of extraction, the ergot is desirably first nely ground, in a suitable mill; andthen putinthe thimble Il. The groundr 40 ergot may be immediately extracted withliquid sulphur dioxide; but we prefer iirst to defat the got, as a preliminary step, before the sulphurdioxide extraction. In the defatting step, a lowboiling petroleum ether may be used, conveniently onewithaboilingpointof 30 to 35 C. For this exh'actim, the petroleum ether is put in the receiver l2, and the condenser Il is conveniently cooled with water. 'Ihe petroleum ether is suitably vaporised, (as byheat from the lamp I9.) in Sotheusualmanner; andthevaporpassesby the lateralpassage Iltothetop ofthe extractor ii and is condensed in the condenser il and drops back upon the ergot Il, in the usual manner of a Soxhlet extractor. 'Ihe extraction with petroleum ether is dedrably continued for from 12 to 24 hours.

After a suicient period of extraction for the dired defatting, the petroleum ether is removed 'from the system. For complete removal, it is oo desirable to spread out the defatted contents of the thimble I3 in a shallow dish, to facilitate evaporation of the petroleum ether; after which the dry and defatted powder is returned to the thimble Il in the extractor Il.

Then an extraction with sulphur dioxide is made. For this, the open-top jacket 2l is filled fairly close to the top with liquid ammonia, which has a boiling point below that of sulphur dioxide. Sulphur dioxide in the gaseous state is admitted 70 through the valve 22 into the condenser Il; and

is there cooled and condensed, so that it drops from the iower end of the condenser on to the ergot Il When a suillcient quantity of liquid sulphur dioxide has been introduced into the system, 75 the valve 22 is closed. 'Ihe liquid sulphur dioxide passesdown through the ergot Il, and through the porous thimble Il, and out by way of the outlet passage I5 into the receiver i2; from which the liquid sulphur dioxide is vaporised to pass upward from the receiver I2 by way of the lateral passage I8 into the upper end of the extractor Ii, to be reliqueiled in the condenser Il and repeat itsvpassage through the ergot. Because of the low boiling point of sulphur dioxide, it is often not necessary to supply any heat tn the receiver l2; although the cycle is speeded up by applying slight heat. as of the electric lamp I9.

'I'he extraction with the sulphur dioxide is desirably continued for from 4 to 8 hours. Then the liquid ammonia in the jacket 2l is removed, or allowed to escape completely: so that the sulphur dioxide in the system may boil oil.

'Ihe residue which remains in the receiver l2 is a brown amorphous powder, and contains the desired ergot alkaloids. It may be used as such; but we prefer to purify it somewhat. This may be done by transferring it to a small Boxhlet extractor, as by repeated washings with low-boiling ligroin, and extracting it in that extractor with ligroin, After two hours of extraction with ligroin, the amorphous residue in the extractor is a iluiIy powder, still brown.

'I'his fluffy brown powder contains the active principle of ergot, and may be administered as such, either in the solid form, conveniently in capsules or inytablets, or in a solution, as in 40% alcohol containing 0.5% tartaric acid. It is oompletely soluble in alcohol. almost completely soluble in ether, and only in part soluble in water.

vThe extraction apparatus which we have described, and some of the steps in the process, are relatively incidental, and may be varied in many ways. The fundamental point is that there shall be an extraction of ergot. whether or not pre- '.viously defatted, by liquid sulphrn' dioxide .at ,relatively low temperature; desirably at not to exceed0C.,forifthepressureinthesystemis raised the temperature of the sulphur dioxide may also be raised, and it is not essential that the extraction be at atmospheric pressure.

The product which we obtain by our p can be administered either orally or parenterally, to produce strong oxytoctic effects. Por parenteraladministration it isnecessarytomake asuitable iluid extract of it, as for instance with a slightly acidulated alcohol-water or glycol-water mixture. For oral administration. it may be used either in the dry form or in such a fluid extract. Various acids may be used, such as hydrochloric, sulphuric, tartaric, lactic, acetic. etc. If administercdin dryform itisusuallyconvenienttoput it in gelatin capsules, or in tablets; which in either case may be either plain or enteric-coated.

The relative actions of ordinary ergot preparations and of an ergot preparation produced by our process are evident from a comparison of Figs. 2 and 3. In each of the, intra-uterine pressureistracedagainsttimebyakymograph apparatus. The intra-uterine pressure is measured in known manner, usually in millimeters of mercury. on human mothers within5to8daysafterdelivery.1'hevertical` dotted line in each view indicates the time of administration of the ergot preparation. Prior to aosasaa When active ergot preparations are administered, they stimulate rhythmic uterine contractions. With former ergot preparations, as shown in Fig. 2 by the kymograph tracing to the right of the vertical dotted line, these rhythmic contractions were with a raised basal line: so that the ,minimum pressure reached between such contractions is above the normal basal line, and the uterus does not become wholly relaxed even between contractions until the eil'ect of the dose has substantially disappeared after a number of hours. In our preparation, in contrast, the rhythmic contractions occur as with previous ergot preparations; but the basal line is not substantially raised, and between successive contractions the uterus substantially wholly relaxes to permit the intra-uterine pressure to drop to the normal basal line, as is indicated in Fig. 3 by the kymograph tracing to the right of the vertical dotted line'.

We claim as our inventionz- 1. A process of obtaining an eiiective ergot preparation, which consists i-n extracting ergot with liquid sulphur dioxide, separating the extract 4so obtained from the ergot residue, and evaporating the sulphur dioxide to leave a solid.

2. A process of obtaining an elective ergot preparation, which consists inf-deiatting ergot. and extracting the defatted ergot with liquid suiphur dioxide, separating the extract so obtained from the ergot residue, and evaporating the sulphur dioxide to leave a solid.

3.'A process of obtaining an eiective ergot preparation, which consists in extracting ergot with liquid sulphur dioxide, separating the extract so obtained from the ergot residue, evaporating the sulphur dioxide, extracting with ligroin the residue left from said evaporation, and separating the then-remaining residue from the ligroin extract.

4. The process of obtaining an eilective ergot preparation, which consists in defattin'g ergot, extracting the defatted ergot with liquid sulphur dioxide, separating the extract so obtained from the ergot residue, evaporating the sulphur dioxide, extracting with ligroin the residue left from said evaporation, and separating the then-remaining residue from the ligroin extract.

MORRIS S. KHARASCH. ROMEO RALPH LEGAULT. 

